Ongoing trials investigating ICIs in thymic epithelial cancer patients (Source: Clinicaltrials.gov)
Combination
Treatment
Identifier/reference
Phase
Setting/line of treatment
Status
Estimated enrollment
Notes
Chemotherapy
Chemotherapy plus pembrolizumab
NCT04554524
II
First line
Recruiting
40
Open label, single group assignment
Single agent
Pembrolizumab
NCT02607631
II
Recurrent
Completed
33
Open label, single group assignment
Nivolumab
NCT03134118
II
Recurrent
Recruiting
55
Open label, single group assignment
Avelumab
NCT03076554
II
Recurrent
Recruiting
55
Open label, single group assignment
Atezolizumab
NCT04321330
II
Recurrent
Recruiting
34
Open label, single group assignment
Radiotherapy
Pembrolizumab, docetaxel, cisplatin therapy followed by surgery/radiotherapy plus pembrolizumab
NCT03858582
II
Neo-adjuvant
Not yet recruiting
40
Non-randomized
Anti-angiogenic
Pembrolizumab plus sunitinib
NCT03463460
II
First line
Recruiting
40
Open label, single group assignment
Nivolumab plus vorolanib
NCT03583086
I/II
First line
Recruiting
177
Open label, single group assignment. thoracic tumors including thymic cancer
Declarations
Author contributions
LC, FP, FM, AL, EL, FP wrote the manuscript and generated the figure and table. JA and RB contributed to the revisions of the manuscript. All authors approved the manuscript for publication.
Conflicts of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Relevant financial activities outside the submitted work: JA reports receiving commercial research grants from Amphera and Roche, holds ownership interest (including patents) in Amphera BV, and is a consultant/advisory board member for Amphera, Boehringer Ingelheim, Bristol-Myers Squibb, Eli-Lilly, MSD, Takeda, Bayer, Astra Zeneca and Roche. RB is a consultant/advisory board member for Astra Zeneca, Boehringer Ingelheim, Novartis, MSD, Otsuka, Eli-Lilly, Roche. The other authors have no conflicts of interest to declare.
Ethical approval
Not applicable.
Consent to participate
Not applicable.
Consent to publication
Not applicable.
Availability of data and materials
Not applicable.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al.; KEYNOTE-024 Investigators. Pembrolizumab vs. chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med.2016;375:1823–33. [DOI] [PubMed]
Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al.; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med.2018;378:2078–92. [DOI] [PubMed]
Cortellini A, Tiseo M, Banna GL, Cappuzzo F, Aerts JGJV, Barbieri F, et al. Clinicopathologic correlates of first-line pembrolizumab effectiveness in patients with advanced NSCLC and a PD-L1 expression of ≥ 50%. Cancer Immunol Immunother.2020;69:2209–21. [DOI] [PubMed]
Cortellini A, Friedlaender A, Banna GL, Porzio G, Bersanelli M, Cappuzzo F, et al. Immune-related adverse events of pembrolizumab in a large real-world cohort of patients with NSCLC with a PD-L1 expression ≥ 50% and their relationship with clinical outcomes. Clin Lung Cancer.2020;21:498–508.e2. [DOI] [PubMed]
Horn L, Mansfield AS, Szczęsna A, Havel L, Krzakowski M, Hochmair MJ, et al.; IMpower133 Study Group. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med.2018;379:2220–9. [DOI] [PubMed]
Paz-Ares L, Dvorkin M, Chen Y, Reinmuth N, Hotta K, Trukhin D, et al.; CASPIAN investigators. Durvalumab plus platinum-etoposide vs. platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet.2019;394:1929–39. [DOI] [PubMed]
Zalcman G, Peters S, Mansfield AS, Jahan TM, Popat S, Scherpereel A, et al. Checkmate 743: a phase 3, randomized, open-label trial of nivolumab (nivo) plus ipilimumab (ipi) vs. pemetrexed plus cisplatin or carboplatin as first-line therapy in unresectable pleural mesothelioma. J Clin Oncol.2017;35Suppl 15:TPS8581. [DOI]
Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J, et al.; KEYNOTE-407 Investigators. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med.2018;379:2040–51. [DOI] [PubMed]
Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab vs. docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med.2015;373:1627–39. [DOI] [PubMed] [PMC]
Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet.2016;387:1540–50. [DOI] [PubMed]
Hann CL, Scherpereel A, Hellyer JA, Wakelee HA.Role of immunotherapy in small cell lung cancer, thymic epithelial tumors, and mesothelioma. Am Soc Clin Oncol Educ Book.2019;39:543–52. [DOI] [PubMed]
Cantini L, Belderbos RA, Gooijer CJ, Dumoulin DW, Cornelissen R, Baart S, et al. Nivolumab in pre-treated malignant pleural mesothelioma: real-world data from the Dutch expanded access program. Transl Lung Cancer Res.2020;9:1169–79. [DOI] [PubMed] [PMC]
Imbimbo M, Maury JM, Garassino M, Girard N; RARECAREnet Working Group. Mesothelioma and thymic tumors: treatment challenges in (outside) a network setting. Eur J Surg Oncol.2019;45:75–80. [DOI] [PubMed]
Pleasance ED, Stephens PJ, O’Meara S, McBride DJ, Meynert A, Jones D, et al. A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature.2010;463:184–90. [DOI] [PubMed] [PMC]
Chan TA, Yarchoan M, Jaffee E, Swanton C, Quezada SA, Stenzinger A, et al. Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic. Ann Oncol.2019;30:44–56. [DOI] [PubMed] [PMC]
Hellmann MD, Callahan MK, Awad MM, Calvo E, Ascierto PA, Atmaca A, et al. Tumor mutational burden and efficacy of nivolumab monotherapy and in combination with ipilimumab in small-cell lung cancer. Cancer Cell.2018;33:853–61.e4. [DOI] [PubMed] [PMC]
George J, Lim JS, Jang SJ, Cun Y, Ozretić L, Kong G, et al. Comprehensive genomic profiles of small cell lung cancer. Nature.2015;524:47–53. [DOI] [PubMed] [PMC]
Hellmann MD, Ott PA, Zugazagoitia J, Ready NE, Hann CL, De Braud FG, et al. Nivolumab (nivo) ± ipilimumab (ipi) in advanced small-cell lung cancer (SCLC): first report of a randomized expansion cohort from CheckMate 032. J Clin Oncol.2017;35Suppl 15:8503. [DOI]
Reck M, Vicente D, Ciuleanu T, Gettinger S, Peters S, Horn L, et al. Efficacy and safety of nivolumab (nivo) monotherapy versus chemotherapy (chemo) in recurrent small cell lung cancer (SCLC): results from CheckMate 331. Ann Oncol.2018;29Suppl 10:X43. [DOI]
Owonikoko TK, Kim HR, Govindan R, Ready N, Reck M, Peters S, et al. Nivolumab (nivo) plus ipilimumab (ipi), nivo, or placebo (pbo) as maintenance therapy in patients (pts) with extensive disease small cell lung cancer (ED-SCLC) after first-line (1L) platinum-based chemotherapy (chemo): results from the double-blind, rando. Ann Oncol.2019;30Suppl 2:ii77. [DOI]
Chung HC, Piha-Paul SA, Lopez-Martin J, Schellens JHM, Kao S, Miller WH Jr, et al. Pembrolizumab after two or more lines of previous therapy in patients with recurrent or metastatic SCLC: results from the KEYNOTE-028 and KEYNOTE-158 studies. J Thorac Oncol.2020;15:618–27. [DOI] [PubMed]
Antonia SJ, López-Martin JA, Bendell J, Ott PA, Taylor M, Eder JP, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol.2016;17:883–95. [DOI] [PubMed]
Tian Y, Zhai X, Han A, Zhu H, Yu J.Potential immune escape mechanisms underlying the distinct clinical outcome of immune checkpoint blockades in small cell lung cancer. J Hematol Oncol.2019;12:67. [DOI] [PubMed] [PMC]
Pavan A, Attili I, Pasello G, Guarneri V, Conte PF, Bonanno L.Immunotherapy in small-cell lung cancer: from molecular promises to clinical challenges. J Immunother Cancer.2019;7:205. [DOI] [PubMed] [PMC]
Rossi A, Di Maio M, Chiodini P, Rudd RM, Okamoto H, Skarlos DV, et al. Carboplatin-or cisplatin-based chemotherapy in first-line treatment of small-cell lung cancer: the COCIS meta-analysis of individual patient data. J Clin Oncol.2012;30:1692–8. [DOI] [PubMed]
Hanna NH, Schneider BJ, Temin S, Baker S Jr, Brahmer J, Ellis PM, et al. Therapy for stage IV non-small-cell lung cancer without driver alterations: ASCO and OH (CCO) joint guideline update. J Clin Oncol.2020;38:1608–32. [DOI] [PubMed]
Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med.2018;378:2288–301. [DOI] [PubMed]
Leonetti A, Wever B, Mazzaschi G, Assaraf YG, Rolfo C, Quaini F, et al. Molecular basis and rationale for combining immune checkpoint inhibitors with chemotherapy in non-small cell lung cancer. Drug Resist Updat.2019;46:100644. [DOI] [PubMed]
Zheng H, Zeltsman M, Zauderer MG, Eguchi T, Vaghjiani RG, Adusumilli PS.Chemotherapy-induced immunomodulation in non-small-cell lung cancer: a rationale for combination chemoimmunotherapy. Immunotherapy.2017;9:913–27. [DOI] [PubMed] [PMC]
Rudin CM, Awad MM, Navarro A, Gottfried M, Peters S, Csőszi T, et al.; KEYNOTE-604 Investigators. Pembrolizumab or placebo plus etoposide and platinum as first-line therapy for extensive-stage small-cell lung cancer: randomized, double-blind, phase III KEYNOTE-604 study. J Clin Oncol.2020;38:2369–79. [DOI] [PubMed] [PMC]
Besse B, Menis J, Bironzo P, Gervais R, Greillier L, Monnet I, et al. REACTION: A phase II study of etoposide and cis/carboplatin with or without pembrolizumab in untreated extensive small cell lung cancer. Ann Oncol.2020;31:S1211–2. [DOI]
Reck M, Luft A, Szczesna A, Havel L, Kim SW, Akerley W, et al. Phase III randomized trial of ipilimumab plus etoposide and platinum versus placebo plus etoposide and platinum in extensive-stage small-cell lung cancer. J Clin Oncol.2016;34:3740–8. [DOI] [PubMed]
López-González A, Diz P, Gutierrez L, Almagro E, Palomo AG, Provencio M.The role of anthracyclines in small cell lung cancer. Ann Transl Med.2013;1:5. [DOI] [PubMed] [PMC]
Sundstrøm S, Bremnes RM, Kaasa S, Aasebø U, Hatlevoll R, Dahle R, et al.; Norwegian Lung Cancer Study Group. Cisplatin and etoposide regimen is superior to cyclophosphamide, epirubicin, and vincristine regimen in small-cell lung cancer: results from a randomized phase III trial with 5 years’ follow-up. J Clin Oncol.2002;20:4665–72. [DOI] [PubMed]
Von Pawel J, Schiller JH, Shepherd FA, Fields SZ, Kleisbauer JP, Chrysson NG, et al. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol.1999;17:658–67. [DOI] [PubMed]
Obeid M, Tesniere A, Ghiringhelli F, Fimia GM, Apetoh L, Perfettini JL, et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med.2007;[Epub ahead of print]. [DOI]
Mankor JM, Zwierenga F, Dumoulin DW, Neefjes JJC, Aerts JGJV.A brief report on combination chemotherapy and anti-programmed death (ligand) 1 treatment in small-cell lung cancer: did we choose the optimal chemotherapy backbone?Eur J Cancer. 2020;137:40–4. [DOI] [PubMed]
Forster M, Moreno V, Calvo E, Olmedo ME, Lopez-Criado MP, Lopez-Vilariño J, et al. Overall survival with lurbinectedin plus doxorubicin in relapsed SCLC. Results from an expansion cohort of a phase Ib trial. J Thorac Oncol.2018;13:S581.
Trigo Perez JM, Leary A, Besse B, Castellano DE, Ponce Aix S, Arrondeau J, et al. Efficacy and safety of lurbinectedin (PM1183) in small cell lung cancer (SCLC): results from a phase 2 study. J Clin Oncol.2018;36Suppl 15:8570. [DOI]
Jiao S, Xia W, Yamaguchi H, Wei Y, Chen MK, Hsu JM, et al. PARP inhibitor upregulates PD-L1 expression and enhances cancer-associated immunosuppression. Clin Cancer Res.2017;23:3711–20. [DOI] [PubMed] [PMC]
Sato H, Niimi A, Yasuhara T, Permata TBM, Hagiwara Y, Isono M, et al. DNA double-strand break repair pathway regulates PD-L1 expression in cancer cells. Nat Commun.2017;8:1751. [DOI] [PubMed] [PMC]
Parkes EE, Walker SM, Taggart LE, McCabe N, Knight LA, Wilkinson R, et al. Activation of STING-dependent innate immune signaling by s-phase-specific DNA damage in breast cancer. J Natl Cancer Inst.2017;109:djw199. [DOI]
Sen T, Rodriguez BL, Chen L, Della Corte CM, Morikawa N, Fujimoto J, et al. Targeting DNA damage response promotes antitumor immunity through STING-mediated T-cell activation in small cell lung cancer. Cancer Discov.2019;9:646–61. [DOI] [PubMed] [PMC]
Krebs M, Ross K, Kim S, De Jonge M, Barlesi F, Postel-Vinay S, et al. An open-label, multitumor phase ii basket study of olaparib and durvalumab (MEDIOLA): results in patients with relapsed SCLC. J Thorac Oncol.2017;12:S2044–5. [DOI]
Thomas A, Vilimas R, Trindade C, Erwin-Cohen R, Roper N, Xi L, et al. Durvalumab in combination with olaparib in patients with relapsed SCLC: results from a phase II study. J Thorac Oncol.2019;14:1447–57. [DOI] [PubMed] [PMC]
Lok BH, Gardner EE, Schneeberger VE, Ni A, Desmeules P, Rekhtman N, et al. PARP inhibitor activity correlates with SLFN11 expression and demonstrates synergy with temozolomide in small cell lung cancer. Clin Cancer Res.2017;23:523–35. [DOI] [PubMed] [PMC]
Stewart CA, Tong P, Cardnell RJ, Sen T, Li L, Gay CM, et al. Dynamic variations in epithelial-to-mesenchymal transition (EMT), ATM, and SLFN11 govern response to PARP inhibitors and cisplatin in small cell lung cancer. Oncotarget.2017;8:28575–87. [DOI] [PubMed] [PMC]
Huang Y, Chen X, Dikov MM, Novitskiy SV, Mosse CA, Yang L, et al. Distinct roles of VEGFR-1 and VEGFR-2 in the aberrant hematopoiesis associated with elevated levels of VEGF. Blood.2007;110:624–31. [DOI] [PubMed] [PMC]
Wu NZ, Klitzman B, Dodge R, Dewhirst MW.Diminished leukocyte-endothelium interaction in tumor microvessels. Cancer Res.1992;52:4265–8. [PubMed]
Gabrilovich DI, Chen HL, Girgis KR, Cunningham HT, Meny GM, Nadaf S, et al. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med.1996;2:1096–103. [DOI] [PubMed]
Huang Y, Yuan J, Righi E, Kamoun WS, Ancukiewicz M, Nezivar J, et al. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc Natl Acad Sci U S A.2012;109:17561–6. [DOI] [PubMed] [PMC]
Tanno S, Ohsaki Y, Nakanishi K, Toyoshima E, Kikuchi K.Human small cell lung cancer cells express functional VEGF receptors, VEGFR-2 and VEGFR-3. Lung Cancer.2004;46:11–9. [DOI] [PubMed]
Schultheis AM, Scheel AH, Ozretić L, George J, Thomas RK, Hagemann T, et al. PD-L1 expression in small cell neuroendocrine carcinomas. Eur J Cancer.2015;51:421–6. [DOI] [PubMed]
Meder L, Schuldt P, Thelen M, Schmitt A, Dietlein F, Klein S, et al. Combined VEGF and PD-L1 blockade displays synergistic treatment effects in an autochthonous mouse model of small cell lung cancer. Cancer Res.2018;78:4270–81. [DOI] [PubMed]
Nan X, Xie C, Yu X, Liu J.EGFR TKI as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer. Oncotarget.2017;8:75712–26. [DOI] [PubMed] [PMC]
Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther.2011;10:2298–308. [DOI] [PubMed]
Yu L, Lai Q, Gou L, Feng J, Yang J.Opportunities and obstacles of targeted therapy and immunotherapy in small cell lung cancer. J Drug Target.2021;29:1–11. [DOI] [PubMed]
Andujar P, Lacourt A, Brochard P, Pairon JC, Jaurand MC, Jean D.Five years update on relationships between malignant pleural mesothelioma and exposure to asbestos and other elongated mineral particles. J Toxicol Environ Health Part B Crit Rev.2016;19:151–72. [DOI]
Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol.2003;21:2636–44. [DOI] [PubMed]
Baas P, Fennell D, Kerr KM, Vn Schil PE, Haas RL, Peters S.Malignant pleural mesothelioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol.2015;26Suppl 5:v31–9. [DOI] [PubMed]
Astoul P, Roca E, Galateau-Salle F, Scherpereel A.Malignant pleural mesothelioma: from the bench to the bedside. Respiration.2012;83:481–93. [DOI] [PubMed]
Kumar T, Patel N, Talwar A.Spontaneous regression of thoracic malignancies. Respir Med.2010;104:1543–50. [DOI] [PubMed]
Yamada N, Oizumi S, Kikuchi E, Shinagawa N, Konishi-Sakakibara J, Ishimine A, et al. CD8+ tumor-infiltrating lymphocytes predict favorable prognosis in malignant pleural mesothelioma after resection. Cancer Immunol Immunother.2010;59:1543–9. [DOI] [PubMed]
Cornelissen R, Lievense LA, Maat AP, Hendriks RW, Hoogsteden HC, Bogers AJ, et al. Ratio of intratumoral macrophage phenotypes is a prognostic factor in epithelioid malignant pleural mesothelioma. PLoS One.2014;9:e106742. [DOI] [PubMed] [PMC]
Mansfield AS, Roden AC, Peikert T, Sheinin YM, Harrington SM, Krco CJ, et al. B7-H1 expression in malignant pleural mesothelioma is associated with sarcomatoid histology and poor prognosis. J Thorac Oncol.2014;9:1036–40. [DOI] [PubMed] [PMC]
Desai A, Karrison T, Rose B, Tan Y, Hill B, Pemberton E, et al. OA08.03 Phase II trial of pembrolizumab (NCT02399371) in previously-treated malignant mesothelioma (MM): final analysis. J Thorac Oncol.2018;13:S339. [DOI]
Quispel-Janssen J, van der Noort V, de Vries JF, Zimmerman M, Lalezari F, Thunnissen E, et al. Programmed death 1 blockade with nivolumab in patients with recurrent malignant pleural mesothelioma. J Thorac Oncol.2018;13:1569–76. [DOI] [PubMed]
Okada M, Kijima T, Aoe K, Kato T, Fujimoto N, Nakagawa K, et al. Clinical efficacy and safety of nivolumab: results of a multicenter, open-label, single-arm, Japanese phase 2 study in malignant pleural mesothelioma (MERIT). Clin Cancer Res.2019;25:5482–92. [DOI]
Hassan R, Thomas A, Nemunaitis JJ, Patel MR, Bennouna J, Chen FL, et al. Efficacy and safety of avelumab treatment in patients with advanced unresectable mesothelioma: phase 1b results from the JAVELIN solid tumor trial. JAMA Oncol.2019;5:351–7. [DOI] [PubMed] [PMC]
Popat S, Curioni-Fontecedro A, Polydoropoulou V, Shah R, O’Brien M, Pope A, et al. LBA91_PRA multicentre randomized phase III trial comparing pembrolizumab (P) vs. single agent chemotherapy (CT) for advanced pre-treated malignant pleural mesothelioma (MPM): results from the European Thoracic Oncology Platform (ETOP 9-15) PROMISE-meso trial. Ann Oncol.2019;30Suppl 5:v931. [DOI]
Fennell DA, Kirkpatrick E, Cozens K, Nye M, Lester J, Hanna G, et al. CONFIRM: a double-blind, placebo-controlled phase III clinical trial investigating the effect of nivolumab in patients with relapsed mesothelioma: study protocol for a randomised controlled trial. Trials.2018;19:233. [DOI] [PubMed] [PMC]
Calabrò L, Morra A, Fonsatti E, Cutaia O, Amato G, Giannarelli D, et al. Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial. Lancet Oncol.2013;14:1104–11. [DOI] [PubMed]
Calabrò L, Morra A, Fonsatti E, Cutaia O, Fazio C, Annesi D, et al. Efficacy and safety of an intensified schedule of tremelimumab for chemotherapy-resistant malignant mesothelioma: an open-label, single-arm, phase 2 study. Lancet Respir Med.2015;3:301–9. [DOI] [PubMed]
Maio M, Scherpereel A, Calabrò L, Aerts J, Perez SC, Bearz A, et al. Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial. Lancet Oncol.2017;18:1261–73. [DOI] [PubMed]
Alley EW, Lopez J, Santoro A, Morosky A, Saraf S, Piperdi B, et al. Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial. Lancet Oncol.2017;18:623–30. [DOI] [PubMed]
Cinausero M, Rihawi K, Cortiula F, Follador A, Fasola G, Ardizzoni A.Emerging therapies in malignant pleural mesothelioma. Crit Rev Oncol Hematol.2019;144:102815. [DOI] [PubMed]
Cantini L, Hassan R, Sterman DH, Aerts JGJV.Emerging treatments for malignant pleural mesothelioma: where are we heading?Front Oncol. 2020;10:343. [DOI] [PubMed] [PMC]
Dozier J, Zheng H, Adusumilli PS.Immunotherapy for malignant pleural mesothelioma: current status and future directions. Transl Lung Cancer Res.2017;6:315–24. [DOI] [PubMed] [PMC]
Rotte A.Combination of CTLA-4 and PD-1 blockers for treatment of cancer. J Exp Clin Cancer Res.2019;38:255. [DOI] [PubMed] [PMC]
Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med.2017;377:1345–56. [DOI] [PubMed] [PMC]
Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, et al. Nivolumab plus ipilimumab vs. sunitinib in advanced renal-cell carcinoma. N Engl J Med.2018;378:1277–90. [DOI] [PubMed] [PMC]
Overman MJ, Lonardi S, Wong KYM, Lenz HJ, Gelsomino F, Aglietta M, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol.2018;36:773–79. [DOI] [PubMed]
Zalcman G, Mazieres J, Greillier L, Brosseau S, Lantuejoul S, Do P, et al. Second/third-line nivolumab vs. nivo plus ipilimumab in malignant pleural mesothelioma: long-term results of IFCT-1501 MAPS2 phase IIR trial with a focus on hyperprogression (HPD). Ann Oncol.2019;30Suppl 5:V747. [DOI]
Calabrò L, Morra A, Giannarelli D, Amato G, D’Incecco A, Covre A, et al. Tremelimumab combined with durvalumab in patients with mesothelioma (NIBIT-MESO-1): an open-label, non-randomised, phase 2 study. Lancet Respir Med.2018;6:451–60. [DOI] [PubMed]
Disselhorst MJ, Quispel-Janssen J, Lalezari F, Monkhorst K, de Vries JF, van der Noort V, et al. Ipilimumab and nivolumab in the treatment of recurrent malignant pleural mesothelioma (INITIATE): results of a prospective, single-arm, phase 2 trial. Lancet Respir Med.2019;7:260–70. [DOI] [PubMed]
Schmid P, Adams S, Rugo HS, Schneeweiss A, Barrios CH, Iwata H, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med.2018;379:2108–21. [DOI] [PubMed]
Marcq E, Audenaerde JRV, Waele J, Jacobs J, Loenhout JV, Cavents G, et al. Building a bridge between chemotherapy and immunotherapy in malignant pleural mesothelioma: investigating the effect of chemotherapy on immune checkpoint expression. Int J Mol Sci.2019;20:4182. [DOI]
Nowak A, Kok P, Lesterhuis W, Hughes B, Brown C, Kao S, et al. OA08.02 DREAM-A phase 2 trial of durvalumab with first line chemotherapy in mesothelioma: final result. J Thorac Oncol.2018;13:S338–9. [DOI]
Forde PM, Sun Z, Anagnostou V, Kindler HL, Purcell WT, Goulart BHL, et al. Phase II multicenter study of anti-PD-L1, durvalumab, in combination with cisplatin and pemetrexed for the first-line treatment of unresectable malignant pleural mesothelioma (MPM)-a PrECOG LLC study. J Clin Oncol.2020;38Suppl 15:9003. [DOI]
Kim JM, Chen DS.Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure). Ann Oncol.2016;27:1492–504. [DOI]
Ohta Y, Shridhar V, Bright RK, Kalemkerian GP, Du W, Carbone M, et al. VEGF and VEGF type C play an important role in angiogenesis and lymphangiogenesis in human malignant mesothelioma tumours. Br J Cancer.1999;81:54–61. [DOI] [PubMed] [PMC]
Garland LL, Chansky K, Wozniak AJ, Tsao AS, Gadgeel SM, Verschraegen CF, et al. Phase II study of cediranib in patients with malignant pleural mesothelioma: SWOG S0509. J Thorac Oncol.2011;6:1938–45. [DOI] [PubMed] [PMC]
Buikhuisen WA, Burgers JA, Vincent AD, Korse CM, van Klaveren RJ, Schramel FM, et al. Thalidomide versus active supportive care for maintenance in patients with malignant mesothelioma after first-line chemotherapy (NVALT 5): an open-label, multicentre, randomised phase 3 study. Lancet Oncol.2013;14:543–51. [DOI] [PubMed]
Buikhuisen WA, Scharpfenecker M, Griffioen AW, Korse CM, Van Tinteren H, Baas P.A randomized phase II study adding axitinib to pemetrexed-cisplatin in patients with malignant pleural mesothelioma: a single-center trial combining clinical and translational outcomes. J Thorac Oncol.2016;11:758–68. [DOI] [PubMed]
Zalcman G, Mazieres J, Margery J, Greillier L, Audigier-Valette C, Moro-Sibilot D, et al. Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial. Lancet.2016;387:1405–14. [DOI] [PubMed]
Girard N, Ruffini E, Marx A, Faivre-Finn C, Peters S; ESMO Guidelines Committee. Thymic epithelial tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol.2015;26Suppl 5:v40–55. [DOI] [PubMed]
Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG, editors. WHO classification of tumours of the lung, pleura, thymus and heart. 4th ed. Lyon: IARC Publications; 2015. [DOI]
den Bakker MA, Roden AC, Marx A, Marino M.Histologic classification of thymoma: a practical guide for routine cases. J Thorac Oncol.2014;9Suppl 2:S125–30. [DOI] [PubMed]
Liu HC, Hsu WH, Chen YJ, Chan YJ, Wu YC, Huang BS, et al. Primary thymic carcinoma. Ann Thorac Surg.2002;73:1076–81. [DOI] [PubMed]
Lamarca A, Moreno V, Feliu J.Thymoma and thymic carcinoma in the target therapies era. Cancer Treat Rev.2013;39:413–20. [DOI] [PubMed]
Ströbel P, Hartmann M, Jakob A, Mikesch K, Brink I, Dirnhofer S, et al. Thymic carcinoma with overexpression of mutated KIT and the response to imatinib. N Engl J Med.2004;350:2625–6. [DOI] [PubMed]
Thomas A, Rajan A, Berman A, Tomita Y, Brzezniak C, Lee MJ, et al. Sunitinib in patients with chemotherapy-refractory thymoma and thymic carcinoma: an open-label phase 2 trial. Lancet Oncol.2015;16:177–86. [DOI] [PubMed] [PMC]
Cheng M, Anderson MS.Thymic tolerance as a key brake on autoimmunity. Nat Immunol.2018;19:659–64. [DOI] [PubMed] [PMC]
Perniola R.Twenty years of AIRE. Frontiers in Immunology. Front Immunol.2018;9:98. [DOI]
Malchow S, Leventhal DS, Nishi S, Fischer BI, Shen L, Paner GP, et al. Aire-dependent thymic development of tumor-associated regulatory T cells. Science.2013;339:1219–24. [DOI] [PubMed] [PMC]
Tseng YC, Hsieh CC, Huang HY, Huang CS, Hsu WH, Huang BS, et al. Is thymectomy necessary in nonmyasthenic patients with early thymoma?J Thorac Oncol. 2013;8:952–8. [DOI] [PubMed]
Marx A, Willcox N, Leite MI, Chuang WY, Schalke B, Nix W, et al. Thymoma and paraneoplastic myasthenia gravis. Autoimmunity.2010;43:413–27. [DOI] [PubMed]
Machens A, Löliger C, Pichlmeier U, Emskötter T, Busch C, Izbicki JR.Correlation of thymic pathology with HLA in myasthenia gravis. Clin Immunol.1999;91:296–301. [DOI] [PubMed]
Radovich M, Pickering CR, Felau I, Ha G, Zhang H, Jo H, et al. The integrated genomic landscape of thymic epithelial tumors. Cancer Cell.2018;33:244–58.e10. [DOI] [PubMed] [PMC]
Giaccone G, Kim C, Thompson J, McGuire C, Kallakury B, Chahine JJ, et al. Pembrolizumab in patients with thymic carcinoma: a single-arm, single-centre, phase 2 study. Lancet Oncol.2018;19:347–55. [DOI] [PubMed]
Cho J, Kim HS, Ku BM, Choi YL, Cristescu R, Han J, et al. Pembrolizumab for patients with refractory or relapsed thymic epithelial tumor: an open-label phase II trial. J Clin Oncol.2019;37:2162–70. [DOI] [PubMed]
Seto T, Katsuya Y, Horinouchi H, Umemura S, Hosomi Y, Satouchi M, et al. Primary result of an investigator-initiated phase II trial of nivolumab for unresectable or recurrent thymic carcinoma: PRIMER study (NCCH1505). J Thorac Oncol.2018;13:S61–2. [DOI]
Rajan A, Heery CR, Thomas A, Mammen AL, Perry S, O’Sullivan Coyne G, et al. Efficacy and tolerability of anti-programmed death-ligand 1 (PD-L1) antibody (Avelumab) treatment in advanced thymoma. J Immunother Cancer.2019;7:269. [DOI] [PubMed] [PMC]
Wei YF, Chu CY, Chang CC, Lin SH, Su WC, Tseng YL, et al. Different pattern of PD-L1, IDO, and FOXP3 Tregs expression with survival in thymoma and thymic carcinoma. Lung Cancer.2018;125:35–42. [DOI] [PubMed]
Ross JS, Gay LM, Wang K, Vergilio JA, Suh J, Ramkissoon S, et al. Comprehensive genomic profiles of metastatic and relapsed salivary gland carcinomas are associated with tumor type and reveal new routes to targeted therapies. Ann Oncol.2017;28:2539–46. [DOI] [PubMed] [PMC]
Rajan A, Girard N, Marx A.State of the art of genetic alterations in thymic epithelial tumors. J Thorac Oncol.2014;9Suppl 2:S131–6. [DOI] [PubMed]
Padda SK, Riess JW, Schwartz EJ, Tian L, Kohrt HE, Neal JW, et al. Diffuse high intensity PD-L1 staining in thymic epithelial tumors. J Thorac Oncol.2015;10:500–8. [DOI] [PubMed] [PMC]
Chen HF, Wu LX, Li XF, Zhu YC, Pan WW, Wang WX, et al. PD-L1 expression level in different thymoma stages and thymic carcinoma: a meta-analysis. Tumori.2020;106:306–11. [DOI] [PubMed]
Funaki S, Shintani Y, Fukui E, Yamamoto Y, Kanzaki R, Ose N, et al. The prognostic impact of programmed cell death 1 and its ligand and the correlation with epithelial-mesenchymal transition in thymic carcinoma. Cancer Med.2019;8:216–26. [DOI] [PubMed] [PMC]
Giaccone G, Rajan A, Berman A, Kelly RJ, Szabo E, Lopez-Chavez A, et al. Phase II study of belinostat in patients with recurrent or refractory advanced thymic epithelial tumors. J Clin Oncol.2011;29:2052–9. [DOI] [PubMed] [PMC]
Cimpean AM, Raica M, Encica S, Cornea R, Bocan V.Immunohistochemical expression of vascular endothelial growth factor A (VEGF), and its receptors (VEGFR1, 2) in normal and pathologic conditions of the human thymus. Ann Anat.2008;190:238–45. [DOI] [PubMed]
Arbour KC, Naidoo J, Steele KE, Ni A, Moreira AL, Rekhtman N, et al. Expression of PD-L1 and other immunotherapeutic targets in thymic epithelial tumors. PLoS One.2017;12:e0182665. [DOI] [PubMed] [PMC]
Sheng X, Yan X, Tang B, Chi Z, Cui C, Si L, et al. A phase I clinical trial of CM082 (X-82) in combination with everolimus for treatment of metastatic renal cell carcinoma. J Clin Oncol.2017;35Suppl 15:4575. [DOI]
Yan X, Sheng X, Tang B, Chi Z, Cui C, Si L, et al. Anti-VEGFR, PDGFR, and CSF1R tyrosine kinase inhibitor CM082 (X-82) in combination with everolimus for treatment of metastatic renal cell carcinoma: a phase 1 clinical trial. Lancet Oncol.2017;18:S8. [DOI]
Yue EW, Sparks R, Polam P, Modi D, Douty B, Wayland B, et al. INCB24360 (Epacadostat), a highly potent and selective indoleamine-2,3-dioxygenase 1 (IDO1) inhibitor for immuno-oncology. ACS Med Chem Lett.2017;8:486–91. [DOI] [PubMed] [PMC]
Brochez L, Chevolet I, Kruse V.The rationale of indoleamine 2,3-dioxygenase inhibition for cancer therapy. European Journal of Cancer. Eur J Cancer.2017;76:167–82. [DOI] [PubMed]
Ravaud A, Urva SR, Grosch K, Cheung WK, Anak O, Sellami DB.Relationship between everolimus exposure and safety and efficacy: meta-analysis of clinical trials in oncology. Eur J Cancer.2014;50:486–95. [DOI] [PubMed]
Rajan A, Carter CA, Berman A, Cao L, Kelly RJ, Thomas A, et al. Cixutumumab for patients with recurrent or refractory advanced thymic epithelial tumours: a multicentre, open-label, phase 2 trial. Lancet Oncol.2014;15:191–200. [DOI] [PubMed] [PMC]
Alcala N, Mangiante L, Le-Stang N, Gustafson CE, Boyault S, Damiola F, et al. Redefining malignant pleural mesothelioma types as a continuum uncovers immune-vascular interactions. EBioMedicine.2019;48:191–202. [DOI] [PubMed] [PMC]
Centonze G, Biganzoli D, Prinzi N, Pusceddu S, Mangogna A, Tamborini E, et al. Beyond traditional morphological characterization of lung neuroendocrine neoplasms: in silico study of next-generation sequencing mutations analysis across the four world health organization defined groups. Cancers (Basel).2020;12:2753. [DOI]
Ilie M, Long-Mira E, Bence C, Butori C, Lassalle S, Bouhlel L, et al. Comparative study of the PD-L1 status between surgically resected specimens and matched biopsies of NSCLC patients reveal major discordances: a potential issue for anti-PD-L1 therapeutic strategies. Ann Oncol.2016;27:147–53. [DOI] [PubMed]
McLaughlin J, Han G, Schalper KA, Carvajal-Hausdorf D, Pelekanou V, Rehman J, et al. Quantitative assessment of the heterogeneity of PD-L1 expression in non-small-cell lung cancer. JAMA Oncol.2016;2:46–54. [DOI] [PubMed] [PMC]
Sheng J, Fang W, Yu J, Chen N, Zhan J, Ma Y, et al. Expression of programmed death ligand-1 on tumor cells varies pre and post chemotherapy in non-small cell lung cancer. Sci Rep.2016;6:20090. [DOI] [PubMed] [PMC]
